title: Heat shock protein 20 interacting with phosphorylated Akt reduces doxorubicin-triggered oxidative stress and cardiotoxicity.
abstract: Doxorubicin (DOX) is a widely used antitumor drug, but its application is limited because of its cardiotoxic side effects. Heat shock protein (Hsp)20 has been recently shown to protect cardiomyocytes against apoptosis, induced by ischemia/reperfusion injury or by prolonged beta-agonist stimulation. However, it is not clear whether Hsp20 would exert similar protective effects against DOX-induced cardiac injury. Actually, DOX treatment was associated with downregulation of Hsp20 in the heart. To elucidate the role of Hsp20 in DOX-triggered cardiac toxicity, Hsp20 was first overexpressed ex vivo by adenovirus-mediated gene delivery. Increased Hsp20 levels conferred higher resistance to DOX-induced cell death, compared to green fluorescent protein control. Furthermore, cardiac-specific overexpression of Hsp20 in vivo significantly ameliorated acute DOX-triggered cardiomyocyte apoptosis and animal mortality. Hsp20 transgenic mice also showed improved cardiac function and prolonged survival after chronic administration of DOX. The mechanisms underlying these beneficial effects were associated with preserved Akt phosphorylation/activity and attenuation of DOX-induced oxidative stress. Coimmunoprecipitation studies revealed an interaction between Hsp20 and phosphorylated Akt. Accordingly, BAD phosphorylation was preserved, and cleaved caspase-3 was decreased in DOX-treated Hsp20 transgenic hearts, consistent with the antiapoptotic effects of Hsp20. Parallel ex vivo experiments showed that either infection with a dominant-negative Akt adenovirus or preincubation of cardiomyocytes with the phosphatidylinositol 3-kinase inhibitors significantly attenuated the protective effects of Hsp20. Taken together, our findings indicate that overexpression of Hsp20 inhibits DOX-triggered cardiac injury, and these beneficial effects appear to be dependent on Akt activation. Thus, Hsp20 may constitute a new therapeutic target in ameliorating the cardiotoxic effects of DOX treatment in cancer patients.
authors.affiliation: Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0575, USA. fangg@ucmail.uc.edu
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Zhou
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Guojie
authors.initials: G
authors.lastname: Song
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.forename: Persoulla
authors.initials: P
authors.lastname: Nicolaou
authors.forename: Guoli
authors.initials: G
authors.lastname: Chen
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ren
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D050886:HSP20 Heat-Shock Proteins / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D051381:Rats
chemical_list: D000903:Antibiotics, Antineoplastic; D050886:HSP20 Heat-Shock Proteins; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt